Nicotine is implicated in many of the adverse effects of smoking on pregnancy and fetal development. Besides the pathophysiological consequences, epidemiologic data indicate that individuals exposed to tobacco smoke in utero are more likely to abuse nicotine as adults. Adolescence also is a period of vulnerability to nicotine. Currently, the neurobiological factors underlying the initiation and maintenance of nicotine addiction are not known; this is a critical gap in our knowledge base. Our preliminary studies show that prenatal exposure to nicotine produces long-term effects on nicotine self-administration and the expression of genes related to GABAergic neurotransmission. Our proposed experiments build upon these findings and will generate new and potentially important information on the influence of prenatal and/or adolescent nicotine exposure on nicotine self-administration in the adult rat. Experiment #1 will characterize further the effects of prenatal nicotine exposure on nicotine self-administration in the adult rat. The threshold dose of prenatal nicotine required to alter adult nicotine self-administration will be determined in order to ascertain the consequences of exposure to second-hand smoke. Experiment #2 will test the hypothesis that combined prenatal and peripuberal exposure to nicotine will lead to greater increases in nicotine self- administration, compared to prenatal exposure alone. We also will find whether the peripuberal period is a critical period of vulnerability to nicotine. A critical question is whether exposure to nicotine during development affects only the responses to nicotine. Experiment #3 will test the hypothesis that prenatal and/or peripuberal exposure to nicotine also increases cocaine self-administration. Experiment #4 will begin to elucidate the mechanisms underlying increased nicotine self-administration by evaluating changes in genes related to GABAergic neurotransmission as a consequence of prenatal and/or peripuberal exposure to nicotine. Relevance: Our experiments will yield critical information that might impact the development and implementation of appropriate pharmacologic treatment and intervention strategies for nicotine addiction. In addition, the results may identify potential long-term and potential deleterious effects of current treatment strategies. Using a nicotine patch or nicotine gum to treat pregnant women might reduce their smoking, but increase the vulnerability of their offspring to develop nicotine addiction.